Virus-induced disease occurs as a result of both direct cell destruction due to virus replication and damage to the infected cells by immunological assault. In addition, viruses can also establish persistent infection during which the "classical" hallmarks of virus infection, namely cytolysis and inflammation are not present. Frequently, these chronic viral infections affect cellular differentiated functions, which can disrupt the host homeostasis and lead to disease. Hence persistent viral infections may play hitherto unsuspected role in disease of the nervous, endocrine and immune systems. The long-term goal of this proposal is to understand the mechanisms by which non-lytic viruses persist and induce endocrine and CNS disorders, as well as to develop therapeutic approaches to combat such infections and their associated diseases. To investigate these issues, we study lymphocyte choriomeningitis virus (LCMV), one of the most valuable model systems for the study of viral persistence and associated diseases. The first aim will focus on the molecular mechanisms by which LCMV causes endocrine and central nervous system (CNS) disturbances. We will investigate the interaction the interaction between LCMV and the growth hormone (GH) transactivating factor GHF1 implicated in the viral induced GH deficiency syndrome (GHDS). We will also investigate the mechanisms by which LCMV alters CNS expression of GAP-43, a key molecule in the plasticity processes associated with learning and memory. The second aim will investigate the impact of viral chronic infection on CNS function during the natural course of ageing. We will examine the effect of such infections on synaptic density and plasticity, as well neurotransmitter function and astrocyte gene expression. The third aim will investigate the contribution of single viral gene to a disease process associated with viral persistence. Using a transgenic mouse model, we will examine the effects of the LCMV nucleoprotein on CNS function. The fourth and final aim will focus on the investigation of therapeutic approaches to combat viral persistent infections and associated diseases. Using the LCMV paradigm we will explore the use of antiviral drugs, cytoimmunotherapy and gene therapy to correct endocrine and CNS disorders associated with LCMV persistence in its natural host, the mouse.